1. Field of the Invention
The present invention relates generally to implantable devices, examples of which include stents and grafts. More particularly, the present invention is directed to an improved method of coating an implantable device with a therapeutic substance.
2. Description of the Related Art
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary, vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially press against the atherosclerotic plaque of the lesion to remodel the vessel wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the vessel after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a prosthesis, examples of which include stents and grafts, is implanted.
Stents are scaffoldings, usually cylindrical or tubular in shape, which function to physically hold open and, if desired, to expand the wall of the vessel. Typically stents are capable of being compressed, so that they may be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
Synthetic vascular grafts are vessel-like configurations that may be positioned into the host blood vessel as a replacement for a diseased or occluded segment that has been removed. Alternatively, a graft may be sutured to the host vessel at each end so as to form a bypass conduit around a diseased or occluded segment of the host vessel.
Although stents and grafts are significant innovations in the treatment of occluded vessels, there remains a need for administering therapeutic substances to the treatment site. To provide an efficacious concentration to the treatment site, systemic administration of the therapeutic substance often produces adverse or toxic side effects for the patient. Local delivery is a highly suitable method of treatment, in that smaller levels of therapeutic substances, as compared to systemic dosages, are concentrated at a specific site. Local delivery produces fewer side effects and achieves more effective results.
One technique for the local delivery of therapeutic substances is through the use of medicated coatings on implantable devices. A common method for medicating a prosthesis involves the use of a polymeric carrier coated onto the surface of the prosthesis. A composition is formed by dissolving a therapeutic substance in a solution containing a polymer and a solvent. The composition is applied to the prosthesis using conventional techniques, such as spray-coating or dip-coating. The solvent is then removed, leaving on the prosthesis surface a coating of the polymer and the therapeutic substance impregnated in the polymer.
A shortcoming of the above-described method is the burst effect, in which an initial rapid release of therapeutic substance upon implantation of the prosthesis is followed by a slower, sustained release of therapeutic substance. Of the various factors which contribute to the burst effect, two factors stem from drying a solution-based coating. First, solution-based coating almost invariably results in an asymmetric distribution of therapeutic substance in the matrix. A higher concentration of therapeutic substance exists at the drying surface, or polymer-air interface, since the therapeutic substance concentrates where the solvent was at the end of the drying process. Additionally, a solvent-dried system may result in the therapeutic substance being in an amorphous phase. When the therapeutic substance is amorphous, as opposed to crystalline, the therapeutic substance exists as individual molecules in the matrix. These molecules may diffuse freely without first having to dissolve into the matrix as they would from a more crystalline phase and therefore contribute to the initial burst of therapeutic substance upon implantation of the prosthesis.
Another shortcoming of the above-described method for medicating a prosthesis is that the method does not facilitate processing every therapeutic substance with every polymer and solvent combination. Some therapeutic substances are very delicate and thus cannot tolerate processing in the presence of a solvent and/or a polymer for extended periods of time. This is especially true for peptide-type therapeutic substances, such as actinomycin D and others, having tertiary structure susceptible to transmutation from their native forms.
The present invention provides a method by which implantable devices, such as stents and grafts, may be coated with therapeutic substances such that the burst effect and the transmutation of delicate therapeutic substances are minimized.
In accordance with one embodiment of the present invention, a method of forming a coating onto a surface of a prosthesis, such as a stent or a graft, is provided. The method includes an act of providing a composition including a therapeutic substance and a first fluid in which the therapeutic substance has limited solubility, such that the therapeutic substance is suspended as particles in the composition. The method additionally includes the acts of applying the composition to a surface of the prosthesis and removing the first fluid from the prosthesis to form a coating. A coating for a prosthesis produced in accordance with the above-described method is also provided.
In some embodiments of the method described herein, the composition additionally includes a second fluid capable of dissolving the therapeutic substance, and the act of providing a composition includes the acts of dissolving the therapeutic substance in the second fluid to form a solution and combining the solution with the first fluid. The therapeutic substance thus precipitates out of the solution to form the composition in which the therapeutic substance is suspended as particles. The act of removing the first fluid from the prosthesis also removes the second fluid from the prosthesis.
In some embodiments of the above-described method, the composition additionally comprises a suspension stabilizer to minimize flocculation of the therapeutic substance within the composition.
In other embodiments of the method, the composition additionally comprises a polymer, such as but not limited to, a bioabsorbable polymer, a biomolecule, or biostable polymer.
In still other embodiments, prior to the act of applying the composition to a surface of the prosthesis, the method further includes the act of applying a polymeric primer layer to the surface of the prosthesis. The method may additionally include the act of creating areas of roughness on the polymeric primer layer.
In other embodiments, subsequent to the acts of applying the composition to a surface of the prosthesis and removing the first fluid from the prosthesis, the method further includes the act of applying a polymeric topcoat disposed on at least a portion of the composition on the surface of the prosthesis.